Optimization and Quest of HPMC loaded Stavudine Controlled Release Dosage Development by Central Composite Design utilizing Reduced Factorial Screening Technique

Gangolu, Jyothsna; Balaiah, Sandyapakula; Nandi, Sisir; Roy, Harekrishna

doi:10.1590/s2175-97902022e201144

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Brazilian Journal of Pharmaceutical Sciences

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Article • Braz. J. Pharm. Sci. 58 • 2022 • https://doi.org/10.1590/s2175-97902022e201144 copy

Optimization and Quest of HPMC loaded Stavudine Controlled Release Dosage Development by Central Composite Design utilizing Reduced Factorial Screening Technique

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

The current research focused on screening and finding the significant independent variables in stavudine loaded tablet, followed by optimizing the best formulation using central composite design. The objective of the study to develop stavudine loaded controlled release tablet utilizing reduced factorial design, followed by optimization technique as well as characterization of prepared tablets. Preliminary trial batches were prepared using different grades of hydroxypropyl methylcellulose. The resolution-IV reduced factorial design was selected to screen the significant independent variables in the dosage form design. A total number of eight runs were prepared and responses were recorded. The signified factors identified by half-normal and Pareto chart. The prepared tablets are evaluated for various physiochemical characterizations. Three dependent responses such as hardness, dissolution at 6 hour and 12 hours are considered in optimization process. Later on, drug-polymer interaction study was carried out. The principal of the study design based on finding the best formulation with prefixed set parameter values utilizing the concept of screening technique. It observed that HPMC K15M (57.18 %), HPMC K100 (66.32 %) and PVP K30 (7.97 %) as best composition in a formulation batch would fulfill the predetermined parameter with specific values.

Keywords:
Stavudine controlled release tablet; Optimization technique; Screening technique; Reduced factorial design; Mathematical modeling

Sl.no	Ingredients	Formulations
Sl.no	Ingredients	F1	F2	F3	F4	F5	F6	F7	F8	F9	F10	F11	F12	F13	F14
1	Stavudine	20	20	20	20	20	20	20	20	20	20	20	20	20	20
2	HPMC K4M	80	50	50	80	90	60	_	_	_	_	_	_	_	_
3	HPMC K15M	100	50	_	_	_	_	50	100	50	100	100	_	_	_
4	HPMC K100M	_	80	80	50	_	_	60	80	_	_	40	_	60	90
5	HPMC E5 LV	_	_	50	_	_	80	70	_	80	_	40	100	60	90
6	HPMC E15 LV	_	_	_	50	90	40	_	_	50	80	_	80	60	_
7	PVP K30 (5%)	q.s	q.s	q.s	q.s	q.s	q.s	q.s	q.s	q.s	q.s	q.s	q.s	q.s	q.s
8	Dicalcium phosphate	90	90	90	90	90	90	90	90	90	90	90	90	90	90
9	Mg stearate	5	5	5	5	5	5	5	5	5	5	5	5	5	5
10	Talc	5	5	5	5	5	5	5	5	5	5	5	5	5	5
	Total weight(mg)	300	300	300	300	300	300	300	300	300	300	300	300	300	300

Run	Factor 1	Factor 2	Factor 3	Factor 4	Response 1	Response 2	Response 3
Run	A:HPMC K4M (mg)	B:HPMC K15M (mg)	C:HPMC K100 (mg)	D:PVP K30 (%)	Hardness (Kg/cm²)	Dissolution (6 h) (%)	Dissolution (12 h) (%)
1	40	50	90	10	6	71.9	82.6
2	60	100	40	5	5	72.1	81.9
3	40	100	90	5	4.5	81.2	98.9
4	60	50	90	5	4	78.3	94.7
5	40	50	40	5	3	72.8	87.2
6	40	100	40	10	3.5	77.3	92.1
7	60	50	40	10	3	74.6	83.7
8	60	100	90	10	4	68.5	80.6

Run	Factor 1	Factor 2	Factor 3	Response 1	Response 2	Response 3
Run	A: HPMC K15M (mg)	B: HPMC K100 (mg)	C: PVP K30 (%)	Hardness (kg/cm²)	Dissolution (6 h) (%)	Dissolution (12 h) (%)
1	50	90	10	5.5	72.35	90.12
2	32.9552	65	7.5	3	72	89.6
3	50	90	5	3.5	71.05	87.12
4	75	65	11.704482	5	65.36	84.65
5	75	65	7.5	4.5	62.76	83.35
6	75	65	7.5	4	65.6	84.15
7	75	65	7.5	4.5	69.95	85.36
8	75	107.04482	7.5	5.5	69.15	84.19
9	75	65	7.5	4	69.25	84.97
10	50	40	10	2.5	72.8	91.7
11	75	65	7.5	5.5	67	86.05
12	117.045	65	7.5	5.5	60	81.75
13	75	65	7.5	5	69.25	85.23
14	50	40	5	3	76.1	91.05
15	100	90	10	6.5	65.6	81.78
16	100	40	10	4.5	75.9	85.7
17	75	22.955179	7.5	3.5	79.1	95.3
18	100	40	5	3.5	79.1	94.27
19	100	90	5	4.5	53.05	73.79
20	75	65	3.2955179	4.5	60.15	82.2

Run	Thickness (mm)	Diameter (mm)	Friability (%)	Weight variation (mg)	Hardness (Kg/cm² )	Drug content (%)	Swelling index at 6h (%)	Swelling index at 12h (%)
1	4.19±0.043	8.09±0.063	0.234±0.01	305.45±1.58	5.5±0.2	93.55±1.2	73.12±2.34	77.73±3.08
2	4.01±0.041	8.13±0.083	0.296±0.02	303.05±0286	3±0.9	91.231.5	68.87±3.17	76.53±5.16
3	4.34±0.043	8.02±0.063	0.123±0.01	304.20±1.37	3.5±0.8	96.10±1.3	73.24±4.21	76.89±1.97
4	4.17±0.041	8.1±0.052	0.356±0.01	303.10±3.52	5±0.5	99.25±2.1	73.36±1.55	79.18±6.31
5	4.23±0.046	8.02±0.023	0.358±0.03	301.30±1.94	4.5±0.4	94.29±2.5	73.12±4.01	77.89±3.63
6	4.15±0.049	8.12±0.065	0.215±0.05	305.95±2.58	4±0.1	94.56±1.5	73.81±3.54	80.93±2.62
7	4.22±0.059	8.05±0.065	0.325±0.01	302.95±1.25	4.5±0.5	91.72±2.4	71.75±3.25	78.74±3.04
8	4.38±0.023	8.07±0.056	0.395±0.05	303.40±1.63	5.5±0.8	96.43±1.5	74.58±2.79	80.75±4.72
9	4.15±0.045	8.1±0.064	0.213±0.04	301.95±2.58	4±0.5	97.43±2.0	74.15±1.48	77.06±1.28
10	3.97±0.063	8.60±0.065	0.389±0.05	302.30±0.18	2.5±0.8	92.72±1.6	71.09±4.07	75.69±4.73
11	4.19±0.046	8.59±0.068	0.248±0.01	304.20±0.49	5.5±0.5	95.19±2.5	74.36±1.57	78.13±3.76
12	4.30±0.063	8.10±.065	0.221±0.03	303.20±3.84	5.5±0.8	99.61±2.0	75.86±3.89	79.59±2.44
13	4.21±0.064	8.07±0.068	0.156±0.05	306.60±2.59	5±0.7	91.36±1.5	73.36±1.79	78.13±3.75
14	4.07±0.052	8.02±0.060	0.284±0.06	305.65±0.81	3±0.7	90.43±3.0	68.71±3.72	74.68±2.45
15	4.42±0.051	8.07±0.062	0.165±0.04	302.80±1.73	6.5±0.1	92.61±2.5	74.58±1.38	80.19±1.54
16	4.18±0.032	8.03±0.063	0.389±0.02	303.60±2.78	4.5±0.5	98.94±1.5	73.01±4.15	78.67±4.85
17	4.09±0.065	8.05±0.064	0.289±0.01	305.35±1.28	3.5±0.5	91.78±3.0	70.81±3.67	74.41±3.64
18	4.27±0.045	8.20±.064	0.156±0.05	304.75±1.54	3.5±0.8	97.81±2.5	73.12±2.78	75.98±1.75
19	4.33±0.042	8.08±0.056	0.198±0.01	305.74±0.98	4.5±0.1	98.84±1.0	75.62±1.73	79.54±4.2
20	4.11±0.041	8.08±0.061	0.352±0.03	301.6±2.72	4.5±0.9	96.84±1.5	72.14±3.17	76.55±3.51

ANOVA data for Hardness (R1)
Source	Sum of squares	df	Mean	F-value	p-value
Model	17.1753978	9	1.908378	6.1075855	0.0045794	significant
A-HPMC K15M	5.54798395	1	5.547984	17.755809	0.0017892
B-HPMC K100	7.1239189	1	7.123919	22.799442	0.0007515
C-PVP K30	2.08870755	1	2.088708	6.684715	0.0271597
Adjusted R²	0.7075	CV%	12.70	Adequate precision	10.04
Predicted R²	0.5279	R²	0.8461	Adequate precision	10.04
ANOVA data for dissolution at 6 h (R2)
Model	726.081363	9	80.67571	7.4767354	0.0020823	significant
A-HPMC K15M	110.412431	1	110.4124	10.232628	0.0095103
B-HPMC K100	251.307226	1	251.3072	23.290253	0.0006959
C-PVP K30	19.0088487	1	19.00885	1.761672	0.2139207
Adjusted R²	0.7542	CV%	4.78	Adequate precision	12.79
Predicted R²	0.5718	R²	0.8706	Adequate precision	12.79
ANOVA data for dissolution at 12 h (R3)
Model	427.247681	9	47.47196	14.11194	0.0001422	significant
A-HPMC K15M	103.807116	1	103.8071	30.85863	0.0002424
B-HPMC K100	172.912928	1	172.9129	51.40164	3.03E-05
C-PVP K30	3.78577251	1	3.785773	1.1253925	0.3137095
Adjusted R²	0.8613	CV%	2.13	Adequate precision	15.71
Predicted R²	0.6209	R²	0.9270	Adequate precision	15.71

Number	HPMC K15M (mg)	HPMC K100 (mg	PVP K30 (mg)	Hardness (kg/cm²)	Dissolution (6 h, %)	Dissolution (12 h, %)	Desirability
1	62.40	58.34	8.54	4.05	69.26	87.11	1
2	86.25	51.81	5.86	4.06	69.26	87.08	1
3	57.18	66.32	7.97	4.05	69.27	87.09	1
4	62.47	58.25	8.56	4.05	69.27	87.09	0.9997
5	57.20	66.16	7.94	4.04	69.28	87.08	0.9996
6	62.11	58.69	8.52	4.05	69.25	87.09	0.9996
7	61.94	58.91	8.51	4.04	69.24	87.08	0.9994
8	57.10	66.34	7.93	4.05	69.28	87.09	0.9994
9	61.79	59.11	8.51	4.04	69.23	87.09	0.9993
10	86.50	51.81	5.82	4.04	69.22	87.08	0.9990
11	58.33	64.26	8.11	4.04	69.21	87.09	0.9989
12	58.64	63.76	8.1	4.05	69.21	87.09	0.9987
13	60.86	60.37	8.42	4.05	69.20	87.09	0.9986
14	60.36	61.09	8.37	4.04	69.19	87.09	0.9984
15	59.47	62.42	8.26	4.04	69.19	87.09	0.9983
16	59.77	61.97	8.31	4.04	69.18	87.09	0.9983
17	62.75	58.71	8.53	4.06	69.21	87.01	0.9946
18	65.48	51.92	9.71	4.12	69.26	87.09	0.9896
19	69.01	57.05	7.71	4.04	69.27	86.64	0.9887
20	71.63	56.28	7.42	4.05	69.26	86.57	0.9868
21	74.97	55.28	7.06	4.05	69.27	86.55	0.9863
22	74.05	55.56	7.15	4.04	69.28	86.56	0.9863
23	52.57	74.53	7.15	4.04	69.89	87.08	0.9781

Response	Predicted	Observed	Std Dev	SE Mean	95% CI low	95% CI high	95% TI low	95% TI high
Hardness	4.05832	4.5	0.5884	0.17656	3.68403	4.43262	1.60151	6.51514
Dissolution (6 h)	69.2766	72.52	3.28485	1.33439	66.3034	72.2498	53.3787	85.1744
Dissolution (12 h)	87.0947	90.71	1.83411	0.74506	85.4346	88.7548	78.2181	95.9713

Universidade de São Paulo, Faculdade de Ciências Farmacêuticas Av. Prof. Lineu Prestes, n. 580, 05508-000 S. Paulo/SP Brasil, Tel.: (55 11) 3091-3824 - São Paulo - SP - Brazil
E-mail: bjps@usp.br

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[1] *Correspondence: Mr. Harekrishna Roy. Department of Pharmaceutics. Nirmala College of pharmacy. Mangalagiri (M), Guntur (Dist), Andhra Pradesh, 522503, India. E-mail: hareroy@gmail.com.